Foot-and-mouth disease virus (FMDV) is a highly contagious picornavirus that poses a serious threat to the global livestock industry. This study aimed to investigate the impact of FMDV infection on the memory immune response in pigs and to analyze the role of type II interferon (IFN-γ) in this process. By comparing pigs artificially infected with FMDV and those vaccinated with inactivated FMDV vaccine, we found that FMDV infection significantly suppressed the development of memory T helper (Th) and B cell populations, affecting the memory immune response. Further experiments showed that pretreatment with IFN-γ could counteract the immunosuppression caused by FMDV, and this counteraction was achieved by promoting the expression of three transcription factors: T-bet, Eomes, and Bcl-6. Our findings emphasize the key role of IFN-γ in regulating the host's immune response to FMDV infection and provide new scientific evidence for the development of effective FMDV vaccines.